Combined immunization against TGF-β1 enhances HPV16 E7-specific vaccine-elicited antitumour immunity in mice with grafted TC-1 tumours

Abstract

Therapeutic vaccine appears to be a potential approach for the treatment of human papillomavirus (HPV)-associated tumours, but its efficacy can be dampened by immunosuppressive factors such as transforming growth factor (TGF)-β1. We sought to investigate whether active immunity against TGF-β1 enhances the anti-tumour immunity elicited by an HPV16 E7-specific vaccine that we developed previously. In this study, virus-like particles of hepatitis B virus core antigen were used as vaccine carriers to deliver either TGF-β1 B cell epitopes or E7 cytotoxic T-lymphocyte epitope. The combination of preventive immunization against TGF-β1 and therapeutic immunization with the E7 vaccine significantly reduced the growth of grafted TC-1 tumours in C57 mice, showing better efficacy than immunization with only one of the vaccines. The improved efficacy of combined immunization is evidenced by elevated IFN-γ and decreased IL-4 and TGF-β1 levels in cultured splenocytes, increased E7-specific IFN-γ-expressing splenocytes, and increased numbers of CD4IFN-γ and CD8IFN-γ cells and decreased numbers of Treg (CD4Foxp3) cells in the spleen and tumours. The results strongly indicate that targeting TGF-β1 through active immunization might be a potent approach to enhancing antigen-specific therapeutic vaccine-induced anti-tumour immune efficacy and providing a combined strategy for effective cancer immunotherapy.

Distinct Responsiveness of Tumor-Associated Macrophages to Immunotherapy of Tumors with Different Mechanisms of Major Histocompatibility Complex Class I Downregulation

“…Neither the neutralization of IL-10 or TGF-β nor the inhibition of arginase resulted in the enhancement of our combined IT. These observations differ from studies conducted in tumors induced with parental TC-1 cells, as targeting either IL-10 or TGF-β enhanced the therapeutic effect of various immunotherapies or increased infiltration with an anti-tumor cell population in these tumors [ 61 , 62 , 63 ]. This difference can be caused by the higher resistance of tumors with MHC-I downregulation to IT and the different mechanisms of tumor cell killing.…”

<p>Virus-Like Particles Presenting the FGF-2 Protein or Identified Antigenic Peptides Promoted Antitumor Immune Responses in Mice</p>

“…46 In this study, potential linear B cell epitopes of mouse FGF-2 were screened by synthesizing a set of overlapping peptides covering the whole sequence of FGF-2 molecules. Theoretically, a peptide with 5-6 amino acids can constitute the smallest B cell epitope; 47 however, according to our previous experiences, 48,49 a peptide with a length of 11-15 amino acids holds a great chance to elicit a high titer of antibodies with a high affinity. In this study, we designed and synthesized peptides with a length between 18 and 29 aa and obtained a set of 13 peptides with a peptide overlapping two adjacent peptides to avoid missing any possible linear epitopes at the joint.…”

SQSTM1/p62 regulate breast cancer progression and metastasis by inducing cell cycle arrest and regulating immune cell infiltration

“…Our previous studies demonstrated that TGF-β1- and HPV E7-presented chimeric virus-like particles significantly suppressed tumor growth through TME regulation. 20 , 33 SQSTM1/p62 also participates in regulating the TME via TAMs, which promote tumor growth. Endogenous and exogenous stimuli induce mitochondrial damage in TAMs that results in the production of mitochondrial DNA (mtDNA) and reactive oxygen species (ROS), which directly activate NLRP3 inflammasome-mediated pyroptosis along with production of the tumor-promoting cytokines IL-1β and IL-18.…”

“…model, 1 × 10 6 cells were inoculated into the second breast fat pad. The mice were monitored three times per week for tumor growth using a slide caliper as described previously, 20 and the mice were sacrificed at experiment endpoints. To generate a murine lung metastasis model, mice were intravenously ( i.v. )…”

“…The flow cytometry protocol was previously reported. 20 Briefly, FITC-labeled anti-mouse CD8α and APC-labeled anti-mouse IFN-γ antibodies were used to stain CTLs, FITC-labeled anti-mouse CD4 and APC-labeled anti-mouse IFN-γ antibodies were used to stain Th1 cells, FITC-labeled anti-mouse CD4 and APC-labeled anti-mouse IL-4 antibodies were used to stain Th2, PE-labeled anti-mouse Gr-1 and APC-labeled anti-mouse CD11b antibodies were used to stain MDSCs, PE-labeled anti-mouse Ly6G and APC-labeled anti-mouse CD11b antibodies were used to stain neutrophils in BALF and PE-labeled anti-mouse F4/80 and APC-labeled anti-mouse CD11b antibodies were used to stain macrophages. All flow cytometry antibodies used in this research were purchased from BioLegend, USA.…”